KR102373750B1 - Method for producing low polymerization degree cellulose ether - Google Patents

Abstract

Provided is a method for producing a low polymerization degree cellulose ether that does not require an additive other than an acid in the depolymerization of a high polymerization degree cellulose ether with an acid, has an improved yellow appearance, and has excellent long-term storage stability. Specifically, it is a step of depolymerizing a high degree of polymerization cellulose ether with an acid to obtain a low degree of polymerization cellulose ether mixture, a step of irradiating ultraviolet rays during or after the depolymerization is finished, and a step of neutralizing the acid in the low polymerization degree cellulose ether mixture It provides a method for producing a low polymerization degree cellulose ether comprising at least.

Description

Manufacturing method of low polymerization degree cellulose ether {METHOD FOR PRODUCING LOW POLYMERIZATION DEGREE CELLULOSE ETHER}

The present invention relates to a process for the preparation of low polymerization degree cellulose ethers.

Low polymerization degree cellulose ether is used for film coating etc. in solid preparations, such as a tablet. This film coating is for masking the unpleasant taste of a drug, preventing denaturation of the drug contained, or controlling the dissolution behavior in the digestive tract after taking.

And, since the film coating is performed on the outermost surface of the tablet, it is preferable that the low polymerization degree cellulose ether used for film coating is finished in pure white in consideration of the ease of coloring during formulation and the visual sensation when taking.

The low polymerization degree cellulose ether is obtained by depolymerizing the high polymerization degree cellulose ether prepared by a conventional method so that it can be easily coated.

As a widely used method, an acid is used to depolymerize a high degree of polymerization cellulose ether to a low degree of polymerization cellulose ether. However, in such a method, it is known that the low polymerization degree cellulose ether after depolymerization becomes yellow (yellowing) compared to the high polymerization degree cellulose ether before depolymerization (Japanese Patent Publication No. 2003-503557).

As a method of suppressing yellowing of low polymerization degree cellulose ether, high polymerization degree cellulose ether is brought into contact with an acid such as hydrogen chloride gas or other hydrogen halide gas to depolymerize, and a method for suppressing yellowing of depolymerization product with sulfur dioxide gas (Japanese Patent Laid-Open (Sso) ) 52-152985), a method in which depolymerization is performed in a diluent such as alcohol (Japanese Patent Publication No. 2009-540098), a film coating formulation having a coating layer is irradiated with light containing ultraviolet rays, The method of suppressing yellowing (Unexamined-Japanese-Patent No. 63-185932) etc. are mentioned.

However, in the method disclosed in Japanese Patent Laid-Open No. 52-152985, a depolymerization product is brought into contact with sulfur dioxide to form a new by-product derived from a sulfur-containing compound, so it is not particularly suitable for pharmaceutical use.

In addition, in the method disclosed in Japanese Patent Publication No. 2009-540098, since depolymerization is performed in a diluent such as isopropyl alcohol, a step of separating the diluent from the cellulose ether with low polymerization degree after depolymerization is required, which is not preferable in terms of production efficiency. Not only that, there is a possibility that the diluent remains.

In addition, in the method disclosed in Japanese Patent Application Laid-Open No. 63-185932, the whiteness of the formulation containing cellulose ether is improved by irradiation with ultraviolet rays, but the cellulose ether turns yellow again during long-term storage, resulting in poor storage stability. there was a problem with

In this regard, in the depolymerization of a high polymerization degree cellulose ether by acid, an additive other than an acid is not required, the yellow color of the appearance is improved, and a method for producing a low polymerization degree cellulose ether excellent in long-term storage stability is required. there is.

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining in order to achieve the said objective, the present inventors discovered that low polymerization degree cellulose ether with little yellowing and little change in appearance by long-term storage was obtained, and came to achieve this invention.

According to the present invention, there is provided a step of depolymerizing a high degree of polymerization cellulose ether with an acid to obtain a low degree of polymerization cellulose ether mixture, the step of irradiating ultraviolet rays during or after the depolymerization is completed, and neutralizing the acid in the low degree of polymerization cellulose ether mixture There is provided a method for producing a low polymerization degree cellulose ether comprising at least the step of: In addition, high polymerization degree cellulose ether means cellulose ether before depolymerization, and low polymerization degree cellulose ether means cellulose ether after depolymerization.

According to the present invention, it is possible to obtain a low polymerization degree cellulose ether with little yellowing and little change in appearance due to long-term storage even after depolymerization with an acid for a high polymerization degree cellulose ether.

High polymerization degree cellulose ethers are water-soluble cellulose ethers with improved solubility in water by introduction of a substituent, and nonionic cellulose ethers such as alkyl cellulose, hydroxyalkyl cellulose, hydroxyalkyl alkyl cellulose, and ionic cellulose ether, such as carboxyalkyl cellulose and the like.

Examples of the alkyl cellulose include methyl cellulose having a methoxy group (DS) of 1.0 to 2.2, and ethyl cellulose having an ethoxy group (DS) of 2.0 to 2.6. Examples of the hydroxyalkyl cellulose include hydroxyethyl cellulose having a hydroxyethoxy group (MS) of 0.05 to 3.0, hydroxypropyl cellulose having a hydroxypropoxy group (MS) of 0.05 to 3.3, and the like.

Examples of the hydroxyalkyl alkyl cellulose include hydroxyethyl methyl cellulose having a methoxy group (DS) of 1.0 to 2.2, a hydroxyethoxy group (MS) of 0.1 to 0.6, a methoxy group (DS) of 1.0 to 2.2, hydroxypropoxy and hydroxypropyl methyl cellulose having a period (MS) of 0.1 to 0.6, hydroxyethyl ethyl cellulose having an ethoxy group (DS) of 1.0 to 2.2, and a hydroxyethoxy group (MS) of 0.1 to 0.6.

Examples of the carboxyalkyl cellulose include carboxymethyl cellulose having a carboxymethoxy group (DS) of 0.2 to 2.2.

In addition, DS represents the degree of substitution, and means the average number of hydroxyl groups substituted with alkoxy groups per glucose ring unit of cellulose. MS represents the number of moles of substitution (Molar Substitution), and means the average number of moles of hydroxyalkoxy groups added per glucose ring unit of cellulose.

As a method of measuring the average degree of substitution of these alkoxy groups and hydroxyalkoxy groups, the analysis method regarding methyl cellulose of the Japanese Pharmacopoeia of the 17th revision is mentioned.

The viscosity of the 2 mass % aqueous solution at 20°C of the high polymerization degree cellulose ether preferably exceeds 20 mPa·s, more preferably 50 to 3000 mPa·s, still more preferably 100 to 2000 mPa·s, particularly preferably is from 500 to 1800 mPa·s.

High degree of polymerization (before depolymerization) and low degree of polymerization (after depolymerization) Viscosity measurement of a 2 mass % aqueous solution at 20° C. of cellulose ether can be measured using a B-type viscometer according to JIS Z8803 when the viscosity is 600 mPa·s or more. And, when the viscosity is less than 600 mPa·s, according to JIS K2283-1993, it can be measured using a Ubbelode type viscometer.

As a general method for producing a high polymerization degree cellulose ether, first, an alkali cellulose obtained by bringing an aqueous alkali metal hydroxide solution into contact with pulp is reacted with an etherification agent. An alkali metal hydroxide and an etherification agent may be coexisted and may be reacted with an etherification agent simultaneously with formation of an alkali cellulose, or an etherification agent may be added and reacted after formation of an alkali cellulose. Although there is no restriction|limiting in particular in alkali metal hydroxide, Sodium hydroxide is preferable from an economical viewpoint. In addition, the etherification agent useful for producing the high polymerization degree cellulose ether is not particularly limited, and examples thereof include alkyl halides such as methyl chloride, ethylene oxide, and propylene oxide. After that, it can be purified as necessary, dried as necessary, and pulverized as necessary to obtain a high degree of polymerization cellulose ether.

The purification method and the apparatus used for purification are not particularly limited, but in consideration of cost, washing is preferably performed using water, more preferably hot water (preferably 85°C to 100°C). In addition, since the cellulose ether used for washing|cleaning gels in hot water, it is insoluble in hot water.

The drying method and the apparatus used for drying are not particularly limited, but the temperature of the high polymerization degree cellulose ether during drying is preferably 40 to 80° C. from the viewpoint of obtaining a low polymerization degree cellulose ether with little yellowing.

Although the grinding method and the apparatus used for grinding are not particularly limited, a grinding method capable of grinding in a short time is preferable from the viewpoint of obtaining a low polymerization degree cellulose ether with little yellowing. Examples of the pulverizer that can be pulverized in a short time include an impact pulverizer such as a turbo mill (manufactured by Turbo Kogyo Co., Ltd.) and a Victory mill (manufactured by Hosokawa Micron Co., Ltd.).

The high polymerization degree cellulose ether after pulverization performed as needed is depolymerized with an acid to obtain a low polymerization degree cellulose ether mixture. The acid used for depolymerization is irrespective of the distinction between gas and liquid, and the state and type of solution as long as protons are donated in the case of an aqueous solution. In general, hydrogen chloride gas, an aqueous solution thereof, or an alcohol solution thereof is preferably used. . As for the aqueous solution concentration in the case of using hydrogen chloride aqueous solution, Preferably it is 1-45 mass %, More preferably, the thing of 5-40 mass % can be used.

The mass of the acid to be added is, from the viewpoint of controlling the viscosity of the low polymerization degree cellulose ether, relative to the high polymerization degree cellulose ether, preferably 0.1 to 3.0 mass% as an acid, and more preferably 0.15 to 1.5 mass%.

The internal temperature of the reactor during depolymerization is preferably 40 to 130°C, more preferably 50 to 110°C, still more preferably 60 to 90°C from the viewpoint of controlling the viscosity of the low polymerization degree cellulose ether.

The depolymerization treatment time is not particularly limited as long as the low polymerization degree cellulose ether after depolymerization has a desired aqueous solution viscosity, but is preferably carried out in the range of 0.1 to 4 hours.

In the present invention, by irradiating an ultraviolet ray during or after the depolymerization with an acid, a low polymerization degree cellulose ether with less yellowing can be obtained. Here, the term "during depolymerization with acid" means while depolymerization with acid is in progress, and preferably refers to while heating the inside of the system after adding acid. In addition, after completion of depolymerization with an acid, it means after obtaining desired depolymerization with an acid, Preferably, it means after completion|finish of heating in a system.

As a wavelength of the ultraviolet-ray irradiated to a cellulose ether, from a viewpoint of obtaining a low polymerization degree cellulose ether with little yellowing, Preferably a wavelength of 100-400 nm, More preferably, a wavelength of 100-380 nm can be used. Although it is preferable that the spectral intensity of an ultraviolet region is large as a light source, it is not specifically limited. As a specific light source, a low pressure mercury lamp, a high pressure mercury lamp, a xenon lamp, etc. are mentioned, for example.

In the case of irradiating ultraviolet rays to the cellulose ether during depolymerization by acid, a method of irradiating ultraviolet rays from a light source installed inside or outside the reactor during depolymerization is exemplified. In the case of irradiating ultraviolet rays from an externally installed light source, it is preferable to use a material having a high ultraviolet transmittance, such as quartz glass, from the viewpoint of obtaining a low polymerization degree cellulose ether with little yellowing as a material of the reactor to be used. In addition, from the viewpoint of obtaining a low polymerization degree cellulose ether with little yellowing, it is preferable to continue irradiation with ultraviolet rays during depolymerization, and it is preferable that the cellulose ether is uniformly irradiated with ultraviolet rays.

When ultraviolet ray is irradiated to the low polymerization degree cellulose ether after completion of depolymerization by acid, the reactant after completion of depolymerization is taken out of the reactor and irradiated with ultraviolet rays. UV irradiation methods include, for example, a method in which the reactant after completion of depolymerization is placed on a belt conveyor and allowed to pass under light, a method in which the reactant after completion of depolymerization placed in a container such as a coating pan is rotated while irradiating ultraviolet rays, etc. , as long as the reaction product after the depolymerization is uniformly irradiated with ultraviolet rays is not particularly limited.

The cumulative irradiation amount of ultraviolet rays is preferably 50 J or more per 1 g of the starting highly polymerized cellulose ether to be subjected to depolymerization. When it is less than 50 J, there is a possibility that a low polymerization degree cellulose ether with less yellowing may not be obtained. Although the upper limit of the cumulative irradiation amount is not particularly limited as long as the low polymerization degree cellulose ether after ultraviolet irradiation has a desired whiteness, it is preferably 300 J or less per 1 g of the cellulose ether. The integrated irradiation amount is calculated|required by multiplying the ultraviolet-ray intensity (mW/cm<2>) by the irradiation time (second) here.

The low polymerization degree cellulose ether aqueous solution obtained by depolymerization with an acid and irradiation with ultraviolet rays is neutralized with an alkali such as sodium bicarbonate or sodium carbonate. The pH of the 2 mass % aqueous solution at 20 degreeC of the low polymerization degree cellulose ether after neutralization becomes like this. Preferably it is 6.0-8.0, More preferably, it is 6.5-7.5. By neutralizing after ultraviolet irradiation, a low polymerization degree cellulose ether with little yellowing and little change in appearance due to long-term storage is obtained.

The rate of decrease in viscosity after depolymerization is not particularly limited, but is preferably 60 to 99.9%, more preferably 80 to 99.9%, still more preferably 95 to 99.9%, from the viewpoint of obtaining a low polymerization degree cellulose ether with little yellowing. Here, the viscosity reduction rate after depolymerization refers to the high polymerization degree (before depolymerization) cellulose ether and low polymerization degree (after depolymerization) cellulose ether with respect to the viscosity of a 2 mass % aqueous solution at 20°C of high polymerization degree (before depolymerization) cellulose ether at 20°C. It is defined as the ratio of the difference in viscosity of the 2% by mass aqueous solution of , that is, the viscosity of the 2% by mass aqueous solution at 20°C (viscosity before depolymerization-viscosity after depolymerization)/viscosity before depolymerization.

Example

Hereinafter, although an Example and a comparative example demonstrate this invention in detail, this invention is not limited to a following Example.

Example 1

To a high polymerization degree hydroxypropyl methyl cellulose (methoxy group (DS) 1.89, hydroxypropyl group (MS) 0.24) having a viscosity of 1,240 mPa·s of a 2 mass % aqueous solution at 20°C prepared by a conventional method, 14 mass % hydrochloric acid was added so that it might become 0.4 mass % with respect to the hydroxypropyl methyl cellulose in conversion of hydrogen chloride. This was put into a quartz glass reactor, and the temperature was controlled so that the internal temperature became 80°C, and the depolymerization reaction was started. Simultaneously with the start of the reaction, a high-pressure mercury lamp (HL100G type, manufactured by Sen Tokushu Kogen Co., Ltd.) installed at a distance of 20 cm above the reactor (UV intensity of 150 mW/cm 2 at a distance of 20 cm from the tip of the lamp, irradiation area of 28 cm 2) was used to irradiate UV rays. The depolymerization reaction was performed for 90 minutes, and irradiation with ultraviolet rays was continued during that time. At this time, the cumulative irradiation amount of ultraviolet rays was 22,680J, and the ultraviolet irradiation amount per 1g of cellulose ether was 94.5J. After completion of the depolymerization reaction, sodium bicarbonate was added for neutralization to obtain hydroxypropyl methyl cellulose having a low polymerization degree. When the obtained low polymerization degree hydroxypropyl methyl cellulose was measured based on the measuring method of the 17th revision Japanese Pharmacopoeia, the viscosity of the 2 mass % aqueous solution at 20 degreeC was 3.0 mPa*s, and pH was 6.7. The rate of decrease in viscosity due to depolymerization with acid was {1-(3.0/1240)}×100=99.8%.

The low polymerization degree after depolymerization was 7.4 as a result of measuring the yellowness of the powder of the hydroxypropyl methyl cellulose by an SM color computer SM-4 (manufactured by Suga Shikekki).

The low-polymerization degree hydroxypropyl methyl cellulose after depolymerization was left still for one month at 40°C and 75% RH using a low-temperature constant temperature and humidifier (type TPAV120-20 manufactured by Isuzu Corporation), and the powder yellowness was measured every week. A result is shown in Table 1.

Example 2

To the high polymerization degree hydroxypropyl methyl cellulose similar to that used in Example 1, 14 mass % of hydrochloric acid was added so that it might become 0.4 mass % with respect to the hydroxypropyl methyl cellulose in conversion of hydrogen chloride. This was put into a quartz glass reactor, and the temperature was controlled so that the internal temperature was 80°C, and depolymerization reaction was performed for 90 minutes. After the depolymerization reaction was completed, the reaction product was spread on a petri dish and irradiated with ultraviolet light for 90 minutes with the apparatus described in Example 1 installed at a distance of 20 cm above the petri dish. In the meantime, the reactant was stirred at 30-minute intervals, and the upper and lower sides of the reactant were exchanged. At this time, the cumulative irradiation amount of ultraviolet rays was 22,680J, and the ultraviolet irradiation amount per 1g of cellulose ether was 94.5J. After irradiating with ultraviolet rays for 90 minutes, sodium bicarbonate was added for neutralization to obtain low polymerization degree hydroxypropyl methyl cellulose. When the obtained low polymerization degree hydroxypropyl methyl cellulose was measured based on the measuring method of the 17th revision Japanese Pharmacopoeia, the viscosity of the 2 mass % aqueous solution at 20 degreeC was 3.0 mPa*s, and pH was 6.6. The rate of decrease in viscosity due to depolymerization with acid was {1-(3.0/1240)}×100=99.8%.

In addition, as a result of measuring the yellowness of the powder by the method described in Example 1, it was 7.0.

Low polymerization degree hydroxypropyl methyl cellulose after depolymerization was left still for 1 month under 40 degreeC and 75% RH conditions using the apparatus described in Example 1, and powder yellowness was measured every week. A result is shown in Table 1.

Comparative Example 1

The depolymerization reaction was carried out in the same manner as in Example 1, except that hydroxypropyl methyl cellulose having a high degree of polymerization similar to that used in Example 1 was used as a raw material, and ultraviolet rays were not irradiated with a high-pressure mercury lamp. When the obtained low polymerization degree hydroxypropyl methyl cellulose was measured based on the measuring method of the 17th revision Japanese Pharmacopoeia, the viscosity of the 2 mass % aqueous solution at 20 degreeC was 3.1 mPa*s, and pH was 6.8. The rate of decrease in viscosity due to depolymerization with acid was {1-(3.1/1240)}×100=99.8%. As a result of measuring the yellowness of the powder of the obtained low polymerization degree hydroxypropyl methyl cellulose by the method described in Example 1, it was 9.6.

The low polymerization degree hydroxypropyl methyl cellulose after depolymerization was left still for about 1 month under conditions of 40°C and 75% RH using the apparatus described in Example 1, and the powder yellowness was measured every week. A result is shown in Table 1.

Reference Example 1

To the high polymerization degree hydroxypropyl methyl cellulose similar to that used in Example 1, 14 mass % of hydrochloric acid was added so that it might become 0.4 mass % with respect to the hydroxypropyl methyl cellulose in conversion of hydrogen chloride. This was put into a quartz glass reactor, and the temperature was controlled so that the internal temperature was 80°C, and depolymerization reaction was performed for 90 minutes. After completion of the depolymerization reaction, sodium bicarbonate was added to neutralize the reaction. The pH of the 2 mass % aqueous solution at 20 degreeC of low polymerization degree hydroxypropyl methyl cellulose after depolymerization was 7.0. After neutralization, the reaction product was spread on a petri dish and irradiated with ultraviolet light for 90 minutes with the apparatus described in Example 1 installed 20 cm above the petri dish. At this time, the cumulative irradiation amount of ultraviolet rays was 22,680J, and the ultraviolet irradiation amount per 1g of cellulose ether was 94.5J. The reaction was stirred every 30 minutes, alternating up and down.

When the obtained low polymerization degree hydroxypropyl methyl cellulose was measured based on the measuring method of the 17th revision Japanese Pharmacopoeia, the viscosity of the 2 mass % aqueous solution at 20 degreeC was 3.0 mPa*s. The rate of decrease in viscosity due to depolymerization with acid was {1-(3.0/1240)}×100=99.8%. As a result of measuring the yellowness of the powder of the obtained low polymerization degree hydroxypropyl methyl cellulose by the method described in Example 1, it was 6.8.

Low polymerization degree hydroxypropyl methyl cellulose after depolymerization was left still for 1 month under 40 degreeC and 75% RH conditions using the apparatus described in Example 1, and powder yellowness was measured every week. A result is shown in Table 1.

Claims (4)

A step of depolymerizing a high degree of polymerization cellulose ether with an acid to obtain a low degree of polymerization cellulose ether mixture, comprising: irradiating ultraviolet rays during or after the depolymerization;
Neutralizing acid in the low polymerization degree cellulose ether mixture
A method for producing a low polymerization degree cellulose ether comprising at least a. The method for producing a low polymerization degree cellulose ether according to claim 1, wherein the cumulative irradiation amount of the ultraviolet rays is 50 J or more per 1 g of the high polymerization degree cellulose ether. The viscosity of the 2 mass % aqueous solution at 20 °C of the high polymerization degree cellulose ether and the low polymerization degree cellulose ether with respect to the viscosity of the 2 mass % aqueous solution at 20 °C of the high polymerization degree cellulose ether The method for producing a low polymerization degree cellulose ether, wherein the ratio of the difference, the viscosity reduction rate by depolymerization is 60 to 99.9%. The method for producing a low polymerization degree cellulose ether according to claim 1 or 2, wherein the high degree of polymerization cellulose ether is an alkyl cellulose, a hydroxyalkyl cellulose or a hydroxyalkyl alkyl cellulose.